In the United States, cancer kills more than 1,500 people per day, and costs society over 100 billion dollars per year. Within five years, cancer will be the leading cause of death in the US, responsible for over eight million years of life lost prematurely each year. The chance of developing cancer is proportional to age to the sixth power. Indeed, 60 percent of all cancers in the US occur in persons 65 years of age or older. Although this age group represents only 12 percent of the population now, it will rise to 20 percent by the year 2030. This graying of America will produce corresponding increases in cancer cases and costs. The currently used chemotherapeutic agents are the drugs with the narrowest therapeutic index in all of medicine. Thus, an effective dose of a wide variety of anti-cancer agents is restricted by their non-selective, highly toxic effect on normal tissues. This is an acute problem with the elderly because chemotherapy-related toxicity is far more common in older patients. Thus, there is an urgent need to develop a more specific and less toxic cancer therapy. Since tumor cell survival, growth and metastasis require persistent new blood vessel growth (angiogenesis), a strategy has emerged to treat cancer by inhibiting angiogenesis. Recently, we developed Hunter-Killer peptides (HKPs) that selectively target and induce apoptotic cell death in angiogenic endothelial cells. The prototype peptide has strong anti-tumor activities in mice, and is less toxic than a targeted form of the anti-cancer drug doxorubicin. HKPs are an entirely new class of anti-cancer agents that can be optimized rationally for maximum therapeutic effect by adjusting peptide properties such as length, hydrophobicity, and residue placement. They offer new hope that a more effective and less toxic cancer treatment can be realized. [Four specific aims for the foundation of the current proposed research. The first three of these aims are a 3-phase program of HKP design and evaluation. The Specific Aims are 1) To design new HKPs. 2) To evaluate the in vitro efficacy and toxicity of the new HKPs. 3) To evaluate the in vivo efficacy and toxicity of these improved peptides in (a) a nude mouse model of human breast carcinoma (immunodepressed host) and in (b) a transgenic mouse model of neuroblastoma (immuno-competent host). 4) To provide insight into the mechanism by which our peptides induce cell death (to confirm/reject the putative mitochondira-dependent mechanism). The long-term objective of this proposed research is to bring Hunter-Killer Peptides closer to practical application, and to provide new insight into the mechanism by which they induce targeted cell death in angiogenic endothelial cells.]